Those who desire to develop a safe and effective microbicide continue to look toward drug delivery to provide solutions to user adherence, drug stability, and achieving effective pharmacokinetics of the multiple active agents over an extended duration. Moreover, the knowledge that infection by other sexually transmitted viruses, particularly HSV, increases the risk of HIV acquisition implores the need for developing microbicides that can protect against both viruses. This proposal describes the development and testing of two intravaginal ring (IVR) drug delivery systems for the prevention of HIV and HSV in women: a thermoplastic polyurethane (TPU) IVR and a new osmotic pump (OP) IVR. This latter IVR design, where drug is released from a liquid reservoir, fills the technological gap of sustained delivery of drugs that are otherwise unsuitable for delivery from current IVR technologies (e.g., thermally sensitive, hydrophilic, macromolecular). Several classes of anti-HIV and anti-HSV compounds will be evaluated. In SA1, these compounds will be subjected to preformulation screening of solubility alone and together. Lead members of each class will be selected based on stability and appropriateness of the drug for each delivery system. In SA2, selected leads will be formulated in dual intravaginal ring segments made by extrusion of thermoplastic polyurethanes containing each antiviral agent. Release rate will be measured as a function of loading and IVR composition, and IVR mechanical properties will be matched to IVR products currently on the market. Based on stability data, antiviral activity and toxicity results from Project 1 and CORE B, two compounds will be selected and coformulated in conjoined dual ring segments that codeliver two antivirals simultaneously at concentrations customized to their pharmacokinetics and pharmacodynamics. Additionally, placebo TPU IVRs will be supplied to Project 3 for human safety trials, and drug-loaded TPU IVRs of appropriate size will be provided to Projects 1&3 and CORE B for animal and human studies. In SA3, OP-IVRs will be optimized and verified by release studies of model drug formulation before validating with lead drug formulations selected in Aim 1. Smaller OP-IVRs will be tested in macaques (PK/PD) in CORE B.